Annu. Rev. Immunol. 2003. 21:659–84 doi: 10.1146/annurev.immunol.21.120601.141036 Copyright c  2003 by Annual Reviews. All rights reserved MOLECULAR INTERACTIONS MEDIATING TCELL ANTIGEN RECOGNITION P. Anton van der Merwe 1 and Simon J. Davis 2 1 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK; email: anton.vandermerwe@path.ox.ac.uk 2 Nuffield Department of Clinical Medicine, University of Oxford, Oxford Radcliffe Hospital, Oxford OX3 9DU; email: sdavis@molbiol.ox.ac.uk Key Words T cell receptor, coreceptor, costimulation, accessory molecules ■ Abstract Over the past decade, key protein interactions contributing to T cell antigen recognition have been characterized in molecular detail. These have included interactions involving the T cell antigen receptor (TCR) itself, its coreceptors CD4 and CD8, the accessory molecule CD2, and the costimulatory receptors CD28 and CTLA-4. A clear view is emerging of how these molecules interact with their ligands at the cell- cell interface. Structural and binding studies have confirmed that the proteins span small but comparable distances and that, overall, they interact very weakly. However, there have been important surprises as well: that TCR interactions with peptide-MHC are topologically constrained and characterized by considerable conformational flexibility at the binding interface; that coreceptors engage peptide-MHC with extraordinarily fast kinetics and at angles apparently precluding direct interactions with the TCR bound to the same peptide-MHC; that the structural mechanisms allowing recognition by costimulatory and accessory molecules to be weak and yet specific are very hetero- geneous; and that because of differences in both binding affinity and stoichiometry, there is enormous variation in the stability of the various costimulatory receptor/ligand complexes. These studies provide the necessary framework for exploring how these molecular interactions initiate T cell activation. INTRODUCTION Antigen recognition by T cells is the key event controlling the adaptive immune response. Its importance has made it the focus of intense study, making it possibly the best-understood cell-cell recognition process. Following an initial period when attention was directed at identifying the various molecules that contribute to T cell antigen recognition, in the past decade attention has shifted to understanding the mechanisms underlying antigen recognition. A key requirement for such under- standing is a detailed characterization of the structure and binding properties of each molecular interaction. In recent years considerable progress has been made in characterizing four key sets of interactions, and we review this progress here. 0732-0582/03/0407-0659$14.00 659 Annu. Rev. Immunol. 2003.21:659-684. Downloaded from arjournals.annualreviews.org by University of Oxford - Nuffield College on 07/02/09. For personal use only.